Is ALG9 p.Ile497Val (c.1489A>G) pathogenic?

ALG9 p.Ile497Val (c.1489A>G) is classified Conflicting classifications of pathogenicity in ALG9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.1244); Ultra-rare (popmax 0.0333%, amr); Associated with Gillessen-Kaesbach-Nishimura syndrome.

What condition is associated with ALG9 p.Ile497Val (c.1489A>G)?

ALG9 p.Ile497Val (c.1489A>G) is associated with Gillessen-Kaesbach-Nishimura syndrome, ALG9-congenital disorder of glycosylation (ClinVar).

How common is ALG9 p.Ile497Val (c.1489A>G) in the general population?

ALG9 p.Ile497Val (c.1489A>G) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

How is ALG9-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALG9 p.Ile497Val (c.1489A>G)?

AlphaMissense predicts likely benign (score 0.1244) — an in-silico prediction, not a clinical call.

ALG9 p.Ile497Val

c.1489A>G · rs138584071 · VCV1366237

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1244 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Gillessen-Kaesbach-Nishimura syndrome

Computational evidence

Protein change
AlphaMissense	0.1244	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.028 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I490V vs ClinVar I497V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,020 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0174% 281/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0224%	4,465
European (non-Finnish)	0.0195%	5,130
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.0141%	7,113
African / African-American	0.00666%	15,006
East Asian	0.00223%	44,872
South Asian	0.0011%	91,078

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALG9
Protein: p.Ile497Val
Coding: c.1489A>G
MANE Select: NM_024740
dbSNP: rs138584071
Type: single nucleotide variant
Location: chr11:111836278 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35 · 2 PDB

Full ALG9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Gillessen-Kaesbach-Nishimura syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG9-congenital disorder of glycosylation

For ALG9-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG9 c.566-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG9 c.896-2A>G Likely pathogenic ★★ same condition
ALG9 p.Arg143Ter Pathogenic/Likely pathogenic ★★ same condition
ALG9 p.Trp248Ter Pathogenic/Likely pathogenic ★★ same condition
ALG9 p.Tyr287Cys Pathogenic/Likely pathogenic ★★ same condition
ALG9 c.*1607C>T Uncertain significance ★★ same condition
ALG9 c.*1624A>C Uncertain significance ★★ same condition
ALG9 c.*1722C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alg9-p-ile497val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown